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Inhibition of Drug Resistance Mechanisms Improves the Benzyl Isothiocyanate–Induced Anti-Proliferation in Human Colorectal Cancer Cells

  • Food Factors: Molecular Targets, mechanisms, pharmacology and in vivo efficacy (D-X Hou, Section Editor)
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Abstract

Purpose of Review

This short review is aimed at summarizing our recent findings about the regulating role of PI3K in the benzyl isothiocyanate (BITC)–induced drug-resistant mechanisms in human colorectal cancer cells and identification of potential components to overcome this resistance by combinatory utilization.

Recent Findings

Benzyl isothiocyanate (BITC), the organosulfur compounds derived from cruciferous vegetables, exerts anti-proliferative effects in various human cancer cells. BITC also enhances the activation of the phosphoinositide 3-kinase (PI3K)/Akt survival pathway, possibly through the inhibition of the protein tyrosine phosphatase 1B. Since the PI3K/Akt pathway as well as drug efflux mediates resistance against anti-cancer drugs, it is important to find an agent to improve the anti-cancer effects of BITC without enhancing the side effects. We have shown that inhibition of PI3K or depletion of the plasma membrane cholesterol significantly enhanced the BITC-induced apoptosis, coinciding with inhibition of the survival pathway. Furthermore, BITC induced autophagy concomitantly with the up-regulation of the nuclear factor–erythroid 2 (NF-E2)–related factor 2 (Nrf2) and Nrf2-dependent cytoprotective genes in human colorectal cancer cells. Experiments using PI3K inhibitors implicated that PI3K is involved not only in the accumulation of autophagic molecules but also the up-regulation of Nrf2 with p62/sequestosome-1. PI3K might play pivotal roles in the resistant mechanisms, such as the activation of cell survival signaling and autophagy-dependent drug metabolism in human colon cancer cells.

Summary

Our studies suggest that combinatory treatment of PI3K inhibitors or cholesterol-depleting agents is a promising strategy to improve the BITC-induced anti-cancer effects in human colorectal cancer cells.

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Funding

This study was partly supported by MEXT KAKENHI Grant Numbers 17H03818 and 20H02933 (YN).

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  1. Xiaoyang Liu and Qifu Yang contributed equally to this work.

Authors and Affiliations

  1. Graduate School of Environmental and Life Science, Okayama University, Okayama, 700-8530, Japan

    Xiaoyang Liu, Qifu Yang & Yoshimasa Nakamura

  2. School of Food Science and Technology, Dalian Polytechnic University, Dalian, 116034, China

    Xiaoyang Liu

  3. National Engineering Research Center of Seafood, Dalian, 116034, China

    Xiaoyang Liu

  4. College of Life and Environmental Sciences, Hunan University of Arts and Science, Changde, 415000, China

    Qifu Yang

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  1. Xiaoyang Liu
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Correspondence to Yoshimasa Nakamura.

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Liu, X., Yang, Q. & Nakamura, Y. Inhibition of Drug Resistance Mechanisms Improves the Benzyl Isothiocyanate–Induced Anti-Proliferation in Human Colorectal Cancer Cells. Curr Pharmacol Rep 6, 306–314 (2020). https://doi.org/10.1007/s40495-020-00227-4

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